PUBLICATION
Biallelic missense variants in ZBTB11 can cause intellectual disability in human
- Authors
- Fattahi, Z., Sheikh, T.I., Musante, L., Rasheed, M., Taskiran, I.I., Harripaul, R., Hu, H., Kazeminasab, S., Alam, M.R., Hosseini, M., Larti, F., Ghaderi, Z., Celik, A., Ayub, M., Ansar, M., Haddadi, M., Wienker, T.F., Ropers, H.H., Kahrizi, K., Vincent, J.B., Najmabadi, H.
- ID
- ZDB-PUB-180613-6
- Date
- 2018
- Source
- Human molecular genetics 27(18): 3177-3188 (Journal)
- Registered Authors
- Celik, Arzu
- Keywords
- none
- MeSH Terms
-
- Animals
- Disease Models, Animal
- Drosophila melanogaster/genetics
- Gene Expression Regulation
- Gene Knockdown Techniques
- HEK293 Cells
- Humans
- Intellectual Disability/genetics*
- Intellectual Disability/pathology
- Mutation, Missense/genetics
- Nervous System/metabolism*
- Nervous System/pathology
- Phenotype
- Protein Binding
- Repressor Proteins/genetics*
- Spinal Cord/metabolism*
- Spinal Cord/pathology
- Zebrafish/genetics
- Zebrafish Proteins/genetics*
- PubMed
- 29893856 Full text @ Hum. Mol. Genet.
Citation
Fattahi, Z., Sheikh, T.I., Musante, L., Rasheed, M., Taskiran, I.I., Harripaul, R., Hu, H., Kazeminasab, S., Alam, M.R., Hosseini, M., Larti, F., Ghaderi, Z., Celik, A., Ayub, M., Ansar, M., Haddadi, M., Wienker, T.F., Ropers, H.H., Kahrizi, K., Vincent, J.B., Najmabadi, H. (2018) Biallelic missense variants in ZBTB11 can cause intellectual disability in human. Human molecular genetics. 27(18):3177-3188.
Abstract
Exploring genes and pathways underlying Intellectual Disability (ID) provides insight into brain development and function, clarifying the complex puzzle of how cognition develops. As part of ongoing systematic studies to identify candidate ID genes, linkage analysis and next generation sequencing revealed ZBTB11, as a novel candidate ID gene. ZBTB11 encodes a less-studied transcription regulator and the two identified missense variants in this study may disrupt canonical Zn2+-binding residues of its C2H2 zinc finger domain, leading to possible altered DNA binding. Using HEK293T cells transfected with wild type and mutant GFP-ZBTB11 constructs, we found the ZBTB11 mutants being excluded from the nucleolus, where the wild-type recombinant protein is predominantly localized. Pathway analysis applied to ChIP-seq data deposited in the ENCODE database supports the localization of ZBTB11 in nucleoli, highlighting associated pathways such as rRNA synthesis, ribosomal assembly, RNA modification, stress sensing and provides a direct link between subcellular ZBTB11 location and its function. Furthermore, considering the report of prominent brain and spinal cord degeneration in a zebrafish Zbtb11 mutant, we investigated ZBTB11-ortholog knockdown in Drosophila melanogaster brain by targeting RNAi using the UAS/Gal4 system. The observed approximate reduction to a third of the mushroom body size - possibly through neuronal reduction or degeneration - may affect neuronal circuits in the brain that are required for adaptive behavior, specifying the role of this gene in nervous system. In conclusion, we report two ID families segregating ZBTB11 biallelic mutations disrupting Zn2+-binding motifs, and provide functional evidence linking ZBTB11 dysfunction to this phenotype.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping